Chemical design of amyloid targeting fluorescent probes Project Summary Deposition of amyloid plaques in the brain represents a universal feature of many neurodegenerative diseases and precedes their clinical symptoms by several years. Thus, the specific detection of amyloid plaques can be used as a biomarker for the diagnosis of neurodegeneration, allowing the opportunity for disease-modifying therapeutic intervention. We have recently designed a new family of fluorescent probes that can label amyloids in tissue. Importantly, our results demonstrate, for the first time, that these probes enhance visualization of amyloids and also make it possible to colorimetrically differentiate the amyloids as a function of their protein composition. This unique ability may enable accurate diagnosis/monitoring of specific neurodegenerative diseases, thereby aiding in selection of a proper course of treatment. Here, we propose to evaluate the structural and electronic parameters that allow the rational design of fluorescent probes for amyloid discrimination. This work will result in new information of fundamental significance to the inherent properties of amyloids and immediate applicability to the development of new diagnostics. The specific aims of this proposal are to: a) develop and experimentally test a theoretical model for the rational design of amyloid targeting fluorescent probes (ATFPs); b) use rationally designed ATFPs to characterize amyloids based on their relative permittivity values and develop an ATFP-based fingerprinting assay; c) develop ATFPs with enhanced optical/biological properties by modifying their chemical/electronic structure; and d) evaluate the biophysical properties of ATFPs in solution and in tissue.